The toxicity of environmental chemicals, that is, nontherapeutic agents, to respiratory tissues is described in significant detail throughout this volume. In the vast majority of cases, these environmental toxicants are inhaled chemicals that interact with respiratory cells on a contact basis, after inhalation. There is, however, an ever-expanding repertoire of chemicals that produce selective or specific toxicity to cells within the respiratory system after systemic circulation throughout the biological system. Many of these chemicals are therapeutic agents such as bleomycin (BLM) or amiodarone (AM) and some are nontherapeutic chemicals such as 3-methylindole (3MI), aflatoxin B1 (AFB1), butylated hydroxytoluene (BHT), halogenated hydrocarbons, naphthalenes, paraquat (1,19-dimethyl-4, 49-bipyridilium, PQ), the pyrrolizidine alkaloids (PZAs), and the substituted furans that are ingested and circulated systemically. This chapter deals with chemicals that are known to cause damage to respiratory tissues following exposure and the mechanisms of their toxicity, which is generally mediated by oxidative metabolism of the chemicals to reactive electrophiles by cytochrome P450 enzymes in cells of the respiratory tract. These compounds are generally toxic to nonciliated bronchiolar epithelial cells and alveolar epithelial cells of the gas exchange region, although some agents are highly toxic to nasal epithelial or pulmonary endothelial cells. The purpose of this chapter is to provide chemical and biochemical insights into the generalized mechanisms of toxicity of certain circulating pneumotoxicants, through the enumeration and compilation of a few examples of well-documented, chemically induced lung damage. © 2010 Elsevier Ltd All rights reserved.